Cell Firing Research Articles

Social odors drive hippocampal CA2 place cell responses to social stimuli.

Hippocampal region CA2 is essential for social memory processing. Interaction with social stimuli induces changes in CA2 place cell firing during active exploration and sharp wave-ripples during rest following a social interaction. However, it is unknown whether these changes in firing patterns are caused by integration of multimodal social stimuli or by a specific sensory modality associated with a social interaction. Rodents rely heavily on chemosensory cues in the form of olfactory signals for social recognition processes. To determine the extent to which social olfactory signals contribute to CA2 place cell responses to social stimuli, we recorded CA2 place cells in rats freely exploring environments containing stimuli that included or lacked olfactory content. We found that CA2 place cell firing patterns significantly changed only when social odors were prominent. Also, place cells that increased their firing in the presence of social odors alone preferentially increased their firing during subsequent sharp wave-ripples. Our results suggest that social olfactory cues are essential for changing CA2 place cell firing patterns during and after social interactions. These results support prior work suggesting CA2 performs social functions and shed light on processes underlying CA2 responses to social stimuli.

Subtle changes in Purkinje cell firing in Purkinje cell-specific Dyt1 ΔGAG knock-in mice

DYT1 dystonia is an inherited early-onset generalized dystonia characterized by sustained muscle contractions causing abnormal, repetitive movements or postures. Most DYT1 patients have a heterozygous trinucleotide GAG deletion (ΔGAG) in DYT1/TOR1A, coding for torsinA. Dyt1 heterozygous ΔGAG knock-in (KI) mice or global KI mice show motor deficits and abnormal Purkinje cell firing. However, Purkinje cell-specific heterozygous ΔGAG conditional KI mice (Pcp2-KI) show improved motor performance, reduced sensory-evoked brain activation in the striatum and midbrain, and reduced functional connectivity of the striatum with the anterior medulla. Whether Pcp2-KI mice show similar abnormal Purkinje cell firing as the global KI mice, suggesting a cell-autonomous effect causes the abnormal Purkinje cell firing in the global KI mice, is unknown. We used acute cerebellar slice recording in Pcp2-KI mice to address this issue. The Pcp2-KI mice exhibited no changes in spontaneous firing and intrinsic excitability compared to the control mice. While membrane properties were largely unchanged, the resting membrane potential was slightly hyperpolarized, which was associated with decreased baseline excitability. Our results suggest that the abnormal Purkinje cell firing in the global KI mice was not cell-autonomous and was caused by physiological changes elsewhere in the brain circuits. Our results also contribute to the ongoing research of how basal ganglia and cerebellum interact to influence motor control in normal states and movement disorders.

The function of GABA in the suprachiasmatic nucleus and its effect on circadian rhythm

Gamma-aminobutyric acid (GABA) is one of the neuron transmitters commonly found in mammals. Previous works have proved the inhibitory nature of GABA in many activities it partakes in. However, recent studies have found that GABA could act as an excitatory factor in certain neural pathways especially in the suprachiasmatic nucleus (SCN) region of the hypothalamus. Circadian clock or circadian rhythm is critical among organisms reaction and regulation to the time of day which helps the organisms maintain homeostasis to the changing weather and seasons. This process can be found in nearly all kingdoms of organisms, particularly which is regulated by the SCN region of the hypothalamus in mammals. In recent years, the potential link between GABA and sleep or circadian rhythm became a new topic among many researchers. Studies have found that GABA has an important effect on circadian rhythm. The excitatory or inhibitory effects of GABA in the SCN is dependent on the concentration of intercellular chloride ion, exposure to day-light and several other factors. GABA can also regulate the concentration level of intercellular ion in the SCN and thus achieve the self-regulating GABAergic neurons. The coupling of the circadian rhythms which is the essential process to synchronize the neuron cell firing rate is also mediated by GABA

Quantitative chromatin protein dynamics during replication origin firing in human cells.

Accurate genome duplication requires a tightly regulated DNA replication program, which relies on the fine regulation of origin firing. While the molecular steps involved in origin firing have been determined predominantly in budding yeast, the complexity of this process in human cells has yet to be fully elucidated. Here, we describe a straightforward proteomics approach to systematically analyse protein recruitment to the chromatin during induced origin firing in human cells. Using a specific inhibitor against CHK1 kinase, we induced a synchronised wave of dormant origin firing (DOF) and assessed the S phase chromatin proteome at different time points. We provide time-resolved loading dynamics of 3,269 proteins, including the core replication machinery and origin firing factors. This dataset accurately represents known temporal dynamics of proteins on the chromatin during the activation of replication forks and the subsequent DNA damage due to the hyperactivation of excessive replication forks. Finally, we used our dataset to identify the condensin II subunit NCAPH2 as a novel factor required for efficient origin firing and replication. Overall, we provide a comprehensive resource to interrogate the protein recruitment dynamics of replication origin firing events in human cells.

How Ideas About Context and Remapping Developed in Brooklyn.

In 1979, I joined Jim Ranck's group in Brooklyn and began recording hippocampal neurons. The first project was to record single neurons across three behaviors in different chambers: pellet retrieval on a radial-arm maze, bar-pressing for food reward in an operant chamber, and maternal pup-retrieval in a large home box. We found spatial firing in all three chambers, with a single-neuron's firing pattern unpredictable from one chamber to the next. We interpreted the spatial firing patterns as representing "context." Later, in the 1980s, I began collaborating with Bob Muller (and Jim Ranck). In the first of a pair of 1987 papers, we used computerized data acquisition, recorded in simple, reduced environments to demonstrate robust, stable place cell firing and the characteristic features of firing fields. In the second paper we showed that when a rat is transferred from one environment to another, the set of place cells "remaps." "Remapping" was defined later, in a pair of 1990 papers. "Context" was introduced in the early three-behavior experiment but was not discussed in the 1987 papers. What is the true relationship between the biological observation of "remapping" and the psychological concept of "context"? This difficult question is addressed here and in more detail in our recent paper.

Transsynaptic modulation of cerebellar nuclear cells: theta AC-burst stimulation

Objectives.Transcranial alternating current stimulation (tACS) and its variants are being tested in clinical trials for treatment of neurological disorders, and cerebellar tACS (ctACS) in particular has garnered much interest because of the involvement of the cerebellum in these disorders. The main objective of this study was to investigate the frequency tuning curves for the entrainment of the Purkinje cells (PCs) and the cerebellar nuclear (CN) cells by their axonal projections. In addition, we aimed to investigate the temporal and steady-state characteristics of the PC-CN transsynaptic modulation under clinically relevant stimulation waveforms.Approach.Experiments were conducted in anesthetized rats with the electrical stimulations applied to the cerebellar cortex while the spiking activity of PC and CN cells were recorded extracellularly. The PC-CN modulation was tested in a wide range of AC frequencies (1-1000 Hz). Furthermore, high-frequency AC stimulation (40-400 Hz) repeated at 4 Hz, that we termedtheta AC-Burst Stimulation, was tested for its transient and steady-state responses.Main results. The CN cell firing patterns suggest that the population of projecting PCs that is entrained by the surface stimulation consists of the cells that are entrained in 180° opposite phases to each other. The CN cell spiking activity in general follows the entrainment pattern of the projecting PCs in the transient response. The CN entrainment during the steady-state turns into suppression at high frequencies of the stimulation. The PC responses could be explained with a simple statistical model that suggested that low-frequency (as well as DC) and high-frequency AC modulation may be operating through different neural mechanisms.Significance.High-frequency AC stimulation with a low-frequency envelope can be leveraged to induce CN modulation at theta frequencies. These results may explain some of the clinical findings and provide insight for future clinical trials of ctACS.

Impaired spatial coding and neuronal hyperactivity in the medial entorhinal cortex of aged App NL-G-F mice.

The progressive accumulation of amyloid beta (Aβ) pathology in the brain has been associated with aberrant neuronal network activity and poor cognitive performance in preclinical mouse models of Alzheimer's disease (AD). Presently, our understanding of the mechanisms driving pathology-associated neuronal dysfunction and impaired information processing in the brain remains incomplete. Here, we assessed the impact of advanced Aβ pathology on spatial information processing in the medial entorhinal cortex (MEC) of 18-month App NL-G-F/NL- G-F knock-in (APP KI) mice as they explored contextually novel and familiar open field arenas in a two-day, four-session recording paradigm. We tracked single unit firing activity across all sessions and found that spatial information scores were decreased in MEC neurons from APP KI mice versus those in age-matched C57BL/6J controls. MEC single unit spatial representations were also impacted in APP KI mice. Border cell firing preferences were unstable across sessions and spatial periodicity in putative grid cells was disrupted. In contrast, MEC border cells and grid cells in Control mice were intact and stable across sessions. We then quantified the stability of MEC spatial maps across sessions by utilizing a metric based on the Earth Mover's Distance (EMD). We found evidence for increased instability in spatially-tuned APP KI MEC neurons versus Controls when mice were re-exposed to familiar environments and exposed to a novel environment. Additionally, spatial decoding analysis of MEC single units revealed deficits in position and speed coding in APP KI mice in all session comparisons. Finally, MEC single unit analysis revealed a mild hyperactive phenotype in APP KI mice that appeared to be driven by narrow-spiking units (putative interneurons). These findings tie Aβ-associated dysregulation in neuronal firing to disruptions in spatial information processing that may underlie certain cognitive deficits associated with AD.

Trading Place for Space: Increasing Location Resolution Reduces Contextual Capacity in Hippocampal Codes.

Many animals learn cognitive maps of their environment - a simultaneous representation of context, experience, and position. Place cells in the hippocampus, named for their explicit encoding of position, are believed to be a neural substrate of these maps, with place cell "remapping" explaining how this system can represent different contexts. Briefly, place cells alter their firing properties, or "remap", in response to changes in experiential or sensory cues. Substantial sensory changes, produced, e.g., by moving between environments, cause large subpopulations of place cells to change their tuning entirely. While many studies have looked at the physiological basis of remapping, we lack explicit calculations of how the contextual capacity of the place cell system changes as a function of place field firing properties. Here, we propose a geometric approach to understanding population level activity of place cells. Using known firing field statistics, we investigate how changes to place cell firing properties affect the distances between representations of different environments within firing rate space. Using this approach, we find that the number of contexts storable by the hippocampus grows exponentially with the number of place cells, and calculate this exponent for environments of different sizes. We identify a fundamental trade-off between high resolution encoding of position and the number of storable contexts. This trade-off is tuned by place cell width, which might explain the change in firing field scale along the dorsal-ventral axis of the hippocampus. We demonstrate that clustering of place cells near likely points of confusion, such as boundaries, increases the contextual capacity of the place system within our framework and conclude by discussing how our geometric approach could be extended to include other cell types and abstract spaces.

Genetic and functional adaptations and alcohol-biased signaling in the mediodorsal thalamus of alcohol dependent mice.

Alcohol Use Disorder (AUD) is a significant health concern characterized by an individual's inability to control alcohol intake. With alcohol misuse increasing and abstinence rates declining, leading to severe social and health consequences, it is crucial to uncover effective treatment strategies for AUD by focusing on understanding neuroadaptations and cellular mechanisms. The mediodorsal thalamus (MD) is a brain region essential for cognitive functioning and reward-guided choices. However, the effects of alcohol (ethanol) dependence on MD neuroadaptations and how dependence alters MD activity during choice behaviors for alcohol and a natural reward (sucrose) are not well understood. Adult C57BL/6J mice treated with chronic intermittent ethanol (CIE) exposure were used to assess genetic and functional adaptations in the MD. Fiber photometry-based recordings of GCaMP6f expressed in the MD of C57BL/6J mice were acquired to investigate in vivo neural adaptations during choice drinking sessions for alcohol (15%) and either water or sucrose (3%). There were time-dependent changes in cFos and transcript expression during acute withdrawal and early abstinence. Differentially expressed genes were identified in control mice across different circadian time points and when comparing control and alcohol dependent mice. Gene Ontology enrichment analysis of the alcohol-sensitive genes revealed disruption of genes that control glial function, axonal myelination, and protein binding. CIE exposure also increased evoked firing in MD cells at 72 hours of withdrawal. In alcohol-dependent male and female mice that show increased alcohol drinking and preference for alcohol over water, we observed an increase in alcohol intake and preference for alcohol when mice were given a choice between alcohol and sucrose. Fiber photometry recordings demonstrated that MD activity is elevated during and after licking bouts for alcohol, water, and sucrose, and the signal for alcohol is significantly higher than that for water or sucrose during drinking. The elevated signal during alcohol bouts persisted in alcohol dependent mice. These findings demonstrate that CIE causes genetic and functional neuroadaptations in the MD and that alcohol dependence enhances alcohol-biased behaviors, with the MD uniquely responsive to alcohol, even in dependent mice.

Category boundaries modulate memory in a place-cell-like manner

Concepts describe how instances of the same kind are related, enabling the categorization and interpretation of new information.1,2 How concepts are represented is a longstanding question. Category boundaries have been considered defining features of concept representations, which can guide categorical inference,3 with fMRI evidence showing category-boundary signals in the hippocampus.4,5 The underlying neural mechanism remains unclear. The hippocampal-entorhinal system, known for its spatially tuned neurons that form cognitive maps of space,6,7 may support conceptual knowledge formation, with place cells encoding locations in conceptual space.4,8,9,10,11 Physical boundaries anchor spatial representations and boundary shifts affect place and grid fields,12,13,14,15,16 as well as human spatial memory,17,18,19 along manipulated dimensions. These place cell responses are likely driven by boundary vector cells, which respond to boundaries at specific allocentric distances and directions,20,21,22,23 the neural correlates of which have been identified in the subiculum and entorhinal cortex20,24,25. We hypothesize similar patterns of memory adaptations in response to shifting category boundaries. Our findings show that after category boundary shifts, participants' memory for category exemplars distorts along the changed dimension, mirroring place field deformations. We demonstrate that the boundary vector cell model of place cell firing best accounts for these distortions compared with alternative geometric explanations. Our study highlights a role of category boundaries in human cognition and establishes a new complementary link between hippocampal coding properties with respect to boundaries and human concept representation, bridging spatial and conceptual domains.

Integration of rate and phase codes by hippocampal cell-assemblies supports flexible encoding of spatiotemporal context.

Spatial information is encoded by location-dependent hippocampal place cell firing rates and sub-second, rhythmic entrainment of spike times. These rate and temporal codes have primarily been characterized in low-dimensional environments under limited cognitive demands; but how is coding configured in complex environments when individual place cells signal several locations, individual locations contribute to multiple routes and functional demands vary? Quantifying CA1 population dynamics of male rats during a decision-making task, here we show that the phase of individual place cells' spikes relative to the local theta rhythm shifts to differentiate activity in different place fields. Theta phase coding also disambiguates repeated visits to the same location during different routes, particularly preceding spatial decisions. Using unsupervised detection of cell assemblies alongside theoretical simulation, we show that integrating rate and phase coding mechanisms dynamically recruits units to different assemblies, generating spiking sequences that disambiguate episodes of experience and multiplexing spatial information with cognitive context.

One-shot entorhinal maps enable flexible navigation in novel environments

Animals must navigate changing environments to find food, shelter or mates. In mammals, grid cells in the medial entorhinal cortex construct a neural spatial map of the external environment1–5. However, how grid cell firing patterns rapidly adapt to novel or changing environmental features on a timescale relevant to behaviour remains unknown. Here, by recording over 15,000 grid cells in mice navigating virtual environments, we tracked the real-time state of the grid cell network. This allowed us to observe and predict how altering environmental features influenced grid cell firing patterns on a nearly instantaneous timescale. We found evidence that visual landmarks provide inputs to fixed points in the grid cell network. This resulted in stable grid cell firing patterns in novel and altered environments after a single exposure. Fixed visual landmark inputs also influenced the grid cell network such that altering landmarks induced distortions in grid cell firing patterns. Such distortions could be predicted by a computational model with a fixed landmark to grid cell network architecture. Finally, a medial entorhinal cortex-dependent task revealed that although grid cell firing patterns are distorted by landmark changes, behaviour can adapt via a downstream region implementing behavioural timescale synaptic plasticity6. Overall, our findings reveal how the navigational system of the brain constructs spatial maps that balance rapidity and accuracy. Fixed connections between landmarks and grid cells enable the brain to quickly generate stable spatial maps, essential for navigation in novel or changing environments. Conversely, plasticity in regions downstream from grid cells allows the spatial maps of the brain to more accurately mirror the external spatial environment. More generally, these findings raise the possibility of a broader neural principle: by allocating fixed and plastic connectivity across different networks, the brain can solve problems requiring both rapidity and representational accuracy.

Social odors drive hippocampal CA2 place cell responses to social stimuli.

Hippocampal region CA2 is essential for social memory processing. Interaction with social stimuli induces changes in CA2 place cell firing during active exploration and sharp wave-ripples during rest following a social interaction. However, it is unknown whether these changes in firing patterns are caused by integration of multimodal social stimuli or by a specific sensory modality associated with a social interaction. Rodents rely heavily on chemosensory cues in the form of olfactory signals for social recognition processes. To determine the extent to which social olfactory signals contribute to CA2 place cell responses to social stimuli, we recorded CA2 place cells in rats freely exploring environments containing stimuli that included or lacked olfactory content. We found that CA2 place cell firing patterns significantly changed only when social odors were prominent. Also, place cells that increased their firing in the presence of social odors alone preferentially increased their firing during subsequent sharp wave-ripples. Our results suggest that social olfactory cues are essential for changing CA2 place cell firing patterns during and after social interactions. These results support prior work suggesting CA2 performs social functions and shed light on processes underlying CA2 responses to social stimuli.

A real‐time cognitive map construction method based on the entorhinal‐hippocampal working mechanism of the rat's brain

AbstractThe firing of spatial cells in the entorhinal‐hippocampal structure is believed to enable the formation of a cognitive map for the environment. Inspired by the spatial cognitive mechanism of the rat's brain, the authors proposed a real‐time cognitive map construction method based on the entorhinal‐hippocampal working mechanism. Firstly, based on the physiological properties of the rat's brain, the authors constructed an entorhinal‐hippocampal CA3 neurocomputational model for path integration. Then, the transformation relationship between the cell plate and the real environment is used to solve the robot's position. Path integration inevitably generates cumulative errors, which require loop‐closure detection and pose optimisation to eliminate errors. To solve the problem that the RatSLAM algorithm is slow in pose optimisation, the authors proposed a pose optimisation method based on a multi‐layer CA1 place cell to improve the speed of pose optimisation. To validate the method, the authors designed simulation experiments, dataset experiments, and physical experiments. The experimental results showed that compared to other brain‐like SLAM algorithms, the authors’ method possesses outstanding performance in path integration accuracy and map construction speed. As a result, the authors’ method can endow mobile robots with the ability to quickly and accurately construct cognitive maps in complex and unknown environments.

Cell firing between ON alpha retinal ganglion cells and coupled amacrine cells in the mouse retina.

Gap junctions are channels that allow for direct transmission of electrical signals between cells. However, the ability of one cell to be impacted or controlled by other cells through gap junctions remains unclear. In this study, heterocellular coupling between ON α retinal ganglion cells (α-RGCs) and displaced amacrine cells (ACs) in the mouse retina was used as a model. The impact of the extent of coupling of interconnected ACs on the synchronized firing between coupled ON α-RGC-AC pair was investigated using the dopamine 1 receptor (D1R) antagonist-SCH23390 and agonist-SKF38393. It was observed that the synchronized firing between the ON α-RGC-ACs pairs was increased by the D1R antagonist SCH23390, whereas it was eradicated by the agonist SKF38393. Subsequently, the signaling drive was investigated by infecting coupled ON α-RGC-AC pairs with the channelrhodopsin-2(ChR2) mutation L132C engineered to enhance light sensitivities. The results demonstrated that the spikes of ON α-RGCs (without ChR2) could be triggered by ACs (with ChR2) through the gap junction, and vice versa. Furthermore, it was observed that ON α-RGCs stimulated with 3-10 Hz currents by whole cell patch could elicit synchronous spikes in the coupled ACs, and vice versa. This provided direct evidence that the firing of one cell could be influenced by another cell through gap junctions. However, this phenomenon was not observed between OFF α-RGC pairs. The study implied that the synchronized firing between ON α-RGC-AC pairs could potentially be affected by the coupling of interconnected ACs. Additionally, one cell type could selectively control the firing of another cell type, thereby forcefully transmitting information. The key role of gap junctions in synchronizing firing and driving cells between α-RGCs and coupled ACs in the mouse retina was highlighted.NEW & NOTEWORTHY This study investigates the role of gap junctions in transmitting electrical signals between cells and their potential for cell control. Using ON α retinal ganglion cells (α-RGCs) and amacrine cells (ACs) in the mouse retina, the researchers find that the extent of coupling between ACs affects synchronized firing. Bidirectional signaling occurs between ACs and ON α-RGCs through gap junctions.

Tropospheric ozone effect on olfactory perception and olfactory bulb dopaminergic interneuron excitability

Ozone (O3) forms in the Earth’s atmosphere, both naturally and by reactions of man-made air pollutants. Deleterious effects of O3 have been found in the respiratory system. Here, we examine whether O3 alters olfactory behavior and cellular properties in the olfactory system. For this purpose, mice were exposed to O3 at a concentration found in highly polluted city air [0.8 ppm], and the behavior elicited by social and non-social odors in habituation/dishabituation tests was assessed. In addition, the electrical responses of dopaminergic olfactory bulb (OB) neurons were also evaluated. O3 differentially compromises olfactory perception to odors: it reduces responses to social and non-social odors in Swiss Webster mice, while this effect was observed in C57BL/6 J mice only for some non-social odors. Additionally, O3 reduced the rate of spontaneous spike firing in periglomerular dopaminergic cells (PG-DA) of the OB. Because this effect could reflect changes in excitability and/or synaptic inputs, the ability of O3 to alter PG-DA spontaneous activity was also tested together with cell membrane resistance, membrane potential, rheobase and chronaxie. Taken together, our data suggest the ability of O3 to affect olfactory perception.

Deletion of the α2δ-1 calcium channel subunit increases excitability of mouse chromaffin cells.

High voltage-gated Ca2+ channels (HVCCs) shape the electrical activity and control hormone release in most endocrine cells. HVCCs are multi-subunit protein complexes formed by the pore-forming α1 and the auxiliary β, α2δ and γ subunits. Four genes code for the α2δ isoforms. At the mRNA level, mouse chromaffin cells (MCCs) express predominantly the CACNA2D1 gene coding for the α2δ-1 isoform. Here we show that α2δ-1 deletion led to ∼60% reduced HVCC Ca2+ influx with slower inactivation kinetics. Pharmacological dissection showed that HVCC composition remained similar in α2δ-1-/- MCCs compared to wild-type (WT), demonstrating that α2δ-1 exerts similar functional effects on all HVCC isoforms. Consistent with reduced HVCC Ca2+ influx, α2δ-1-/- MCCs showed reduced spontaneous electrical activity with action potentials (APs) having a shorter half-maximal duration caused by faster rising and decay slopes. However, the induced electrical activity showed opposite effects with α2δ-1-/- MCCs displaying significantly higher AP frequency in the tonic firing mode as well as an increase in the number of cells firing AP bursts compared to WT. This gain-of-function phenotype was caused by reduced functional activation of Ca2+-dependent K+ currents. Additionally, despite the reduced HVCC Ca2+ influx, the intracellular Ca2+ transients and vesicle exocytosis or endocytosis were unaltered in α2δ-1-/- MCCs compared to WT during sustained stimulation. In conclusion, our study shows that α2δ-1 genetic deletion reduces Ca2+ influx in cultured MCCs but leads to a paradoxical increase in catecholamine secretion due to increased excitability. KEY POINTS: Deletion of the α2δ-1 high voltage-gated Ca2+ channel (HVCC) subunit reduces mouse chromaffin cell (MCC) Ca2+ influx by ∼60% but causes a paradoxical increase in induced excitability. MCC intracellular Ca2+ transients are unaffected by the reduced HVCC Ca2+ influx. Deletion of α2δ-1 reduces the immediately releasable pool vesicle exocytosis but has no effect on catecholamine (CA) release in response to sustained stimuli. The increased electrical activity and CA release from MCCs might contribute to the previously reported cardiovascular phenotype of patients carrying α2δ-1 loss-of-function mutations.

Perineuronal Nets in the Rat Medial Prefrontal Cortex Alter Hippocampal-Prefrontal Oscillations and Reshape Cocaine Self-Administration Memories.

The medial prefrontal cortex (mPFC) is a major contributor to relapse to cocaine in humans and to reinstatement in rodent models of cocaine use disorder. The output from the mPFC is potently modulated by parvalbumin (PV)-containing fast-spiking interneurons, the majority of which are surrounded by perineuronal nets. We previously showed that treatment with chondroitinase ABC (ABC) reduced the consolidation and reconsolidation of a cocaine conditioned place preference memory. However, self-administration memories are more difficult to disrupt. Here we report in male rats that ABC treatment in the mPFC attenuated the consolidation and blocked the reconsolidation of a cocaine self-administration memory. However, reconsolidation was blocked when rats were given a novel, but not familiar, type of retrieval session. Furthermore, ABC treatment prior to, but not after, memory retrieval blocked reconsolidation. This same treatment did not alter a sucrose memory, indicating specificity for cocaine-induced memory. In naive rats, ABC treatment in the mPFC altered levels of PV intensity and cell firing properties. In vivo recordings from the mPFC and dorsal hippocampus (dHIP) during the novel retrieval session revealed that ABC prevented reward-associated increases in high-frequency oscillations and synchrony of these oscillations between the dHIP and mPFC. Together, this is the first study to show that ABC treatment disrupts reconsolidation of the original memory when combined with a novel retrieval session that elicits coupling between the dHIP and mPFC. This coupling after ABC treatment may serve as a fundamental signature for how to disrupt reconsolidation of cocaine memories and reduce relapse.

Medial entorhinal cortex mediates learning of context-dependent interval timing behavior.

Episodic memory requires encoding the temporal structure of experience and relies on brain circuits in the medial temporal lobe, including the medial entorhinal cortex (MEC). Recent studies have identified MEC 'time cells', which fire at specific moments during interval timing tasks, collectively tiling the entire timing period. It has been hypothesized that MEC time cells could provide temporal information necessary for episodic memories, yet it remains unknown whether they display learning dynamics required for encoding different temporal contexts. To explore this, we developed a new behavioral paradigm requiring mice to distinguish temporal contexts. Combined with methods for cellular resolution calcium imaging, we found that MEC time cells display context-dependent neural activity that emerges with task learning. Through chemogenetic inactivation we found that MEC activity is necessary for learning of context-dependent interval timing behavior. Finally, we found evidence of a common circuit mechanism that could drive sequential activity of both time cells and spatially selective neurons in MEC. Our work suggests that the clock-like firing of MEC time cells can be modulated by learning, allowing the tracking of various temporal structures that emerge through experience.

Onion skin is not a universal firing pattern for spinal motoneurons: simulation study.

Muscle force is modulated by sequential recruitment and firing rates of motor units (MUs). However, discrepancies exist in the literature regarding the relationship between MU firing rates and their recruitment, presenting two contrasting firing-recruitment schemes. The first firing scheme, known as "onion skin," exhibits low-threshold MUs firing faster than high-threshold MUs, forming separate layers akin to an onion. This contradicts the other firing scheme, known as "reverse onion skin" or "afterhyperpolarization (AHP)," with low-threshold MUs firing slower than high-threshold MUs. To study this apparent dichotomy, we used a high-fidelity computational model that prioritizes physiological fidelity and heterogeneity, allowing versatility in the recruitment of different motoneuron types. Our simulations indicate that these two schemes are not mutually exclusive but rather coexist. The likelihood of observing each scheme depends on factors such as the motoneuron pool activation level, synaptic input activation rates, and MU type. The onion skin scheme does not universally govern the encoding rates of MUs but tends to emerge in unsaturated motoneurons (cells firing < their fusion frequency that generates peak force), whereas the AHP scheme prevails in saturated MUs (cells firing at their fusion frequency), which is highly probable for slow (S)-type MUs. When unsaturated, fast fatigable (FF)-type MUs always show the onion skin scheme, whereas S-type MUs do not show either one. Fast fatigue-resistant (FR)-type MUs are generally similar but show weaker onion skin behaviors than FF-type MUs. Our results offer an explanation for the longstanding dichotomy regarding MU firing patterns, shedding light on the factors influencing the firing-recruitment schemes.NEW & NOTEWORTHY The literature reports two contrasting schemes, namely the onion skin and the afterhyperpolarization (AHP) regarding the relationship between motor units (MUs) firing rates and recruitment order. Previous studies have examined these schemes phenomenologically, imposing one scheme on the firing-recruitment relationship. Here, we used a high-fidelity computational model that prioritizes biological fidelity and heterogeneity to investigate motoneuron firing schemes without bias toward either scheme. Our objective findings offer an explanation for the longstanding dichotomy on MU firing patterns.